Age Related Changes in NAD+ Metabolism Oxidative Stress and Sirt1 Activity in Wistar Rats

Abstract

The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of metabolism, stress resistance and longevity. Apart from its role as an important redox carrier, NAD+ also serves as the sole substrate for NAD-dependent enzymes, including poly(ADP-ribose) polymerase (PARP), an important DNA nick sensor, and NAD-dependent histone deacetylases, Sirtuins which play an important role in a wide variety of processes, including senescence, apoptosis, differentiation, and aging. We examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female wistar rats. Our results are the first to show a significant decline in intracellular NAD+ levels and NAD:NADH ratio in all organs by middle age (i.e.12 months) compared to young (i.e. 3 month old) rats. These changes in [NAD(H)] occurred in parallel with an increase in lipid peroxidation and protein carbonyls (o- and m- tyrosine) formation and decline in total antioxidant capacity in these organs. An age dependent increase in DNA damage (phosphorylated H2AX) was also observed in these same organs. Decreased Sirt1 activity and increased acetylated p53 were observed in organ tissues in parallel with the drop in NAD+ and moderate over-expression of Sirt1 protein. Reduced mitochondrial activity of complex I-IV was also observed in aging animals, impacting both redox status and ATP production. The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor.

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Cited by papers we hold 24

• Regulation of SIRT1 and Its Roles in Inflammation · 2022
  No notice
• Mechanisms of impaired mitochondrial homeostasis and NAD+ metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation · 2021
  Not checked
• NAD+ metabolism, stemness, the immune response, and cancer · 2021
  No notice
• Role of NAD+ in regulating cellular and metabolic signaling pathways · 2021
  No notice
• Oxidative Stress in Cognitive and Epigenetic Aging: A Retrospective Glance · 2020
  No notice
• DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation · 2019
  No notice
• Quantitative analysis of the effects of nicotinamide phosphoribosyltransferase induction on the rates of NAD+ synthesis and breakdown in mammalian cells using stable isotope-labeling combined with mass spectrometry. · 2019
  Not checked
• Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies · 2019
  No notice
• The Plasma NAD + Metabolome Is Dysregulated in “Normal” Aging · 2019
  No notice
• Sirt1–hypoxia‐inducible factor‐1α interaction is a key mediator of tubulointerstitial damage in the aged kidney · 2019
  No notice
• Cytoplasmic and Mitochondrial NADPH-Coupled Redox Systems in the Regulation of Aging · 2019
  No notice
• Mitochondria in the signaling pathways that control longevity and health span · 2019
  No notice
• NAD+ biosynthesis, aging, and disease · 2018
  No notice
• High Levels of SIRT1 Expression as a Protective Mechanism Against Disease-Related Conditions · 2018
  No notice
• The emerging role of alternative splicing in senescence and aging · 2017
  No notice
• Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells · 2017
  No notice
• Sirtuins, a promising target in slowing down the ageing process · 2017
  No notice
• Emerging therapeutic roles for NAD + metabolism in mitochondrial and age‐related disorders · 2016
  No notice
• Sirtuin Functions in Female Fertility: Possible Role in Oxidative Stress and Aging · 2015
  No notice
• A remarkable age-related increase in SIRT1 protein expression against oxidative stress in elderly: SIRT1 gene variants and longevity in human. · 2015
  Not checked

and 4 more

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